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Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

Abstract

Neuronal mechanisms underlying alcohol intoxication are unclear. We find that alcohol impairs motor coordination by enhancing tonic inhibition mediated by a specific subtype of extrasynaptic GABAA receptor (GABAR), α6β3δ, expressed exclusively in cerebellar granule cells. In recombinant studies, we characterize a naturally occurring single-nucleotide polymorphism that causes a single amino acid change (R100Q) in α6 (encoded in rats by the Gabra6 gene). We show that this change selectively increases alcohol sensitivity of α6β3δ GABARs. Behavioral and electrophysiological comparisons of Gabra6100R/100R and Gabra6100Q/100Q rats strongly suggest that alcohol impairs motor coordination by enhancing granule cell tonic inhibition. These findings identify extrasynaptic GABARs as critical targets underlying low-dose alcohol intoxication and demonstrate that subtle changes in tonic inhibition in one class of neurons can alter behavior.

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Figure 1: The α6-R100Q polymorphism leads to a marked increase in ethanol sensitivity when expressed with β3 and δ subunits.
Figure 2: A single-nucleotide polymorphism (a guanine-to-adenine substitution) in the gene encoding the rat GABAA receptor α6 subunit (Gabra6) is common in Sprague-Dawley rats obtained from Charles River Laboratories.
Figure 3: Ethanol enhances granule cell tonic GABA current, and the enhancement is larger in Gabra6100Q/100Q rats.
Figure 4: Tonic GABA current in granule cells is enhanced by low concentrations of ethanol in Gabra6100R/100R and Gabra6100Q/100Q rats.
Figure 5: Rats homozygous for the α6-100Q polymorphism show increased alcohol-induced motor impairment as compared with Gabra6100R/100R rats.

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Acknowledgements

We thank C. Gundersen and the UCLA Anesthesiology Department for providing X. laevis oocytes, A. Taylor and D. Tio for help with blood alcohol analysis, and K. Olofsdotter-Otis for helpful comments on the manuscript. The work was supported by a Human Frontiers Science Program Long Term Fellowship to P.D.D. and by US National Institutes of Health grants AA015460 to H.J.H, NS41651 to T.S.O., and NS35985 and AA07680 to R.W.O.

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Correspondence to Thomas S Otis or Martin Wallner.

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Hanchar, H., Dodson, P., Olsen, R. et al. Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity. Nat Neurosci 8, 339–345 (2005). https://doi.org/10.1038/nn1398

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